EP1453835B1 - Antagonistes du recepteur a 2a de l'adenosine - Google Patents

Antagonistes du recepteur a 2a de l'adenosine Download PDF

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Publication number
EP1453835B1
EP1453835B1 EP02784641A EP02784641A EP1453835B1 EP 1453835 B1 EP1453835 B1 EP 1453835B1 EP 02784641 A EP02784641 A EP 02784641A EP 02784641 A EP02784641 A EP 02784641A EP 1453835 B1 EP1453835 B1 EP 1453835B1
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Prior art keywords
alkyl
alkoxy
group
mmol
aryl
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German (de)
English (en)
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EP1453835A2 (fr
Inventor
Julius J. Matasi
John P. Caldwell
Deen Tulshian
Lisa S. Silverman
Bernard R. Neustadt
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to substituted 1,2,4-triazolo[1,5-c]pyrimidine adenosine A 2a receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson's disease, and to pharmaceutical compositions containing said compounds.
  • Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
  • Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins.
  • Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A 1 , A 2a , A 2b and A 3 .
  • a 1 and A 3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A 2a and A 2b are low-affinity, stimulating the activity of the same enzyme.
  • Analogs of adenosine able to interact as antagonists with the A 1 , A 2a , A 2b and A 3 receptors have also been identified.
  • a 2a antagonists for the A 2a receptor are of pharmacological interest because of their reduced level of side affects.
  • a 2a antagonists can have antidepressant properties and stimulate cognitive functions.
  • data has shown that A 2a receptors are present in high density in the basal ganglia, known to be important in the control of movement.
  • a 2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
  • xanthine-related compounds have been found to be A 1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A 2a affinity with varying degrees of A 2a vs. A 1 selectivity.
  • Triazolo-pyrimidine adenosine A 2a receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; US 5,565,460; WO 97/05138; and WO 98/52568.
  • Pyrazolo-substituted triazolo-pyrimidine adenosine A 2a receptor antagonists are disclosed in US 09/207,143, filed May 24, 2001 EP 1 116 722 and EP 0 976 753.
  • This invention relates to compounds having the structural formula I or a pharmaceutically acceptable salt or solvate thereof; wherein:
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a one or more compounds of formula I and one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula I and one or more agents known to be useful in the treatment of Parkinson's in one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention relates to the use of one or more compounds of formula I in the manufacture of a phamaceutical composition for treating stroke or central nervous system diseases.
  • the central nervous system diseases include cognitive diseases or neurodegenerative diseases such as such as Parkinson's disease, senile dementia or psychoses of organic origin.
  • the amount of compound administered to the patient is a therapeutically effective amount.
  • Another aspect of the invention relates to the use of a compound of formula I in the manufacture of a pharmaceutical composition for treating Parkinson's disease with a combination one or more compounds of formula I and one or more agents useful in the treatment of Parkinson's disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase (COMT) inhibitor.
  • one or more compounds of formula I and one or more other anti-Parkinson's agents can be administered simultaneously or sequentially in separate dosage forms.
  • kits comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Parkinson's disease wherein one container comprises a pharmaceutical composition comprising an one or more compounds of formula I in one or more pharmaceutically acceptable carriers, and wherein, in separate containers, one or more pharmaceutical compositions each comprise one or more agents useful in the treatment of Parkinson's disease in one or more pharmaceutically acceptable carriers.
  • This invention relates to compounds having the structural formula I or a pharmaceutically acceptable salt or solvate of said compound, wherein R, R 2 , and R 3 are as defined above.
  • variable e.g., R 2
  • its definition in each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Alkyl (including the alkyl portions of alkoxy, alkylamino, and dialkylamino) means an aliphatic hydrocarbon group which may be straight or branched and comprising 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to about 6 carbon atoms in the chain. Branched alkyl means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Preferred alkyl groups in the present invention are lower alkyl groups.
  • Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, trifluoromethyl and cyclopropylmethyl.
  • Alkyl groups can be substituted with one or more substituents, which may be the same or different, and are selected from the group consisting of alkyl, aryl, heteroaryl, hydroxy, alkoxy, halo, nitro, cyano, and cycloalkyl.
  • Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy.
  • the alkyl group is linked to an adjacent moiety through the ether oxygen.
  • Alkoxyalkyl is a moiety containing an alkoxy linked to the main group via an alkyl.
  • Alkoxycarbonyl means an alkyl-O-C(O)- group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The alkoxy is linked to an adjacent moiety through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O) 2 - group. Preferred groups are those in which the alkyl group is lower alkyl. The alkyl is linked to an adjacent moiety through the sulfonyl.
  • Alkylsulfinyl means an alkyl-S(O)- group. Preferred groups are those in which the alkyl group is lower alkyl. The alkyl is linked to an adjacent moiety through the sulfinyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising 2 to 15 carbon atoms in the chain.
  • Preferred alkenyl groups have 2 to 2 carbon atoms in the chain; and more preferably 2 to 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means 2 to 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, and n-pentenyl.
  • Alkanoyl is an alkyl attached to a carbonyl wherein alkyl has the same meaning as defined above.
  • Alkylene referring to a divalent alkyl group, similarly refers to straight or branched chains.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylamino, arylamino, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, aralkyloxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,
  • Cycloalkyl means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclobutyt, cyclopentyl, cyclohexyl and the like.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomenyl, adamantyl and the like.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • Cycloheteroalkyl means a non-aromatic mono- or multicyclic fused ring system comprising 3 to 10 ring carbon atoms, preferably 3 to 7 ring carbon atoms, more preferably 3 to 6 ring carbon atoms, wherein the cycloheteroalkyl has 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure provided that the rings do not contain adjacent oxygen and/or sulfur atoms.
  • the cycloheteroalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • Aryl means an aromatic monocyclic or mutticyclic ring system comprising 6 to 14 ring carbon atoms, preferably 6 to 10 ring carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl represents cyclic aromatic groups of 5 or 6 ring atoms or bicyclic groups of 11 to 12 ring atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms.
  • Preferred heteroaryls contain 5 to 6 ring atoms.
  • the “heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • Useful 6-membered heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like and the N-oxides thereof.
  • Useful 5-membered heteroaryl rings include furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl and the like.
  • Useful bicyclic groups include benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl, indolyl and the like.
  • Divalent heteroaryl means a heteroaryl ring bonded to two different groups.
  • Y is divalent R 8 -heteroaryl
  • one ring member is attached to the variable X, and another ring member is attached to variable Z; the R 8 substituents are attached to the remaining ring members.
  • Divalent heteroaryl groups are named by adding "diyl" to the name of the ring, for example, a pyridinediyl ring is shown:
  • Arylcarbonyl is an aryl linked to the main group via a carbonyl wherein aryl has the same definition as described above.
  • Alkylaryl is a moiety containing an alkyl linked to the main group or ring via an aryl group.
  • Cycloalkylene refers to a divalent cycloalkyl group.
  • solvate as used herein means an aggregate that consists of a solute ion or molecule with one or more solvent molecules, for example, a hydrate containing such ions.
  • prodrug means a compound that is a drug precursor which, following administration to a patient, releases the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • therapeutically effective amount means an amount sufficient to treat central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson's disease, senile dementia and psychoses of organic origin.
  • the therapeutically effective amount of active compound in a unit dose of preparation can range from about 0.1 mg to about 1000 mg, more preferably from about 1 mg to about 300 mg.
  • Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers).
  • the invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
  • the compounds of formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, such as compound 174 disclosed herein, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylprop
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicydohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines. N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g.
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • These compounds possess antagonistic activity at A 2a receptors and are useful in the treatment of Parkinson's disease and depression. They may be used alone or in combination with dopaminergic agents such as L-DOPA or ropinrole. They may also be used in conjunction with known anti-depressant therapeutic agents.
  • the compounds of formula I are prepared by the methods shown in reaction schemes 1 and 2.
  • the compounds prepared by reaction scheme 3 do not fall within the scope of the invention, and it will be appreciated that the parts of this scheme that relate to compound outside of the scope of the invention are provided by way of showing analogous procedures to those by which compounds of the invention may be made.
  • the desired precursor IX may be prepared either from treatment of the appropriate ketone VII with alkylchloroformate in the presence of base or from the treatment of an appropriate ⁇ -keto ester VIII with R 3 X under basic conditions.
  • the ⁇ -keto ester IX can undergo condensation reaction with guanadine carbonate at elevated temperature in an inert solvent, such as DMF, to produce the amino pyrimidine X.
  • Treatment of X with POCl 3 at elevated temperature affords the chloro analog XI.
  • the treatment of XI with the appropriate hydrazide in butanol at elevated temperature provides a hydrazide XII .
  • Treatment of compounds of formula XII with N, O-bis(trimethylsilyl)acetamide provides compounds of formula I.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula I and one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula I and one or more agents known to be useful in the treatment of Parkinson's in one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention relates to the use of one or more compounds of formula I in the manufacture of a pharmaceutical composition for treating stroke or central nervous system diseases.
  • the central nervous system diseases include cognitive diseases or neurodegenerative diseases such as such as Parkinson's disease, senile dementia or psychoses of organic origin.
  • the invention is drawn to the use of one or more compounds of formula I in the manufacture of a pharmaceutical composition for treating Parkinson's disease
  • the amount of compound administered is a therapeutically effective amount.
  • Another aspect of the invention relates to the use of compound of formula I in the manufacture of a pharmaceutical composition for treating Parkinson's disease with a combination of one or more compounds of formula I and one or more agents useful in the treatment of Parkinson's disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase (COMT) inhibitor.
  • one or more compounds of formula I and one or more other anti-Parkinson's agents can be administered simultaneously or sequentially in separate dosage forms.
  • kits comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Parkinson's disease wherein one container comprises a pharmaceutical composition comprising one or more compounds of formula I in one or more pharmaceutically acceptable carriers, and wherein, in separate containers, one or more pharmaceutical compositions each comprise one or more agents useful in the treatment of Parkinson's disease in one or more pharmaceutically acceptable carriers.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 70 percent by weight of active ingredient, which include compounds of formula I and optionally other compounds useful for treating Parkinson's disease.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and solidify.
  • Liquid form preparations include solutions, suspensions and emulsions.
  • An example of this is water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to about 1000 mg, more preferably from about 1 mg to about 300 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • a typical recommended dosage regimen for compounds of formula I is oral administration of from about 10 mg to about 2000 mg/day preferably from about 10mg to about 1000 mg/day, in two to four divided doses to provide relief from central nervous system diseases such as Parkinson's disease.
  • the compounds are non-toxic when administered within this dosage range.
  • STEP 1 Heat a mixture of 2-amino-4-chloro-6-methylpyrimidine (1.44 g, 10.00 mmol) and 2-furoic hydrazide (1.89 g, 15.0 mmol) in butanol (50 mL) at 90 °C for 16 h.
  • Step 2 Heat the solid produced in Step 1 (0.77 g, 3.30 mmol) in N,O-bis(trimethylsilyl)acetamide (5 mL) at 120 °C overnight. Cool the reaction mixture and pour it on ice water and stir for 4h. Extract the mixture with ethyl acetate dry over sodium sulfate, fitter, and concentrate in vacuo. Purify the residue on silica gel chromatography to produce a solid.
  • 1 H NMR (DMSO-d 6 ) ⁇ 7.83 (br. M. 3H). 7.10 (dd, 1H), 6.75 (s, 1H). 6.64 (dd, 1H). 2.30 (s, 3H). Mass spectrum (ESI): 216.0.
  • Step 2 The product of Step 1 B (9.20 g, 36.27 mmol) was heated in N,O-bis(trimethylsilyl)acetamide (49.4 g, 242.14 mmol) at 120 °C overnight. The reaction mixture was cooled and poured onto ice water and stirred for 4h. The mixture was extracted with ethyl acetate dried over sodium sulfate, filtered, and concentrated in vacuo . The residue was purifed on silica gel chromatography to produce a solid C .
  • Step 3 In a sealed tube, heat the product of Step 2 C (50 mg, 0.21 mmol) with 3,5-Dimethylbenzeneboronic acid (63 mg, 0.42 mmol), Pd (PPh 3 ) 4 (24 mg, 0.02 mmol), and sodium carbonate (74 mg, 2.10 mmol) in a solvent system of 3/1/1//toluene/ethanol/water at 103 °C for a period of 4h. After cooling the reaction mixture to room temperature, the mixture was extracted with EtOAc and water. The organic portion was collected, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to produce a solid D .
  • STEP 1 A mixture of 2-amino-4,6-dichloro-pyrimidine (0.50 g, 3.048 mmol), 3-isopropylbenzeneboronic acid (0.30g, 1.572 mmol), Pd(PPh 3 ) 4 (0.09 g, 0.076 mmol), and 4-10 equivalents of sodium carbonate was heated in a solvent system of 1/1//acetonitrile/water (15 mL) at 90 °C for a period of 4h. The reaction mixture was cooled to room temperature. The mixture was extracted with EtOAc and water. The organic portion was collected, dried over sodium sulfate, filtered, and concentrated in vacuo .
  • Step 2 The product of Step 1 (0.39 g, 1.57 mmol) and 2-furoic hydrazide (0.30 g, 2.36 mmol) in butanol (10 mL) were heated at 120 °C for 5 h. The reaction mixture was cooled to room temperature, and then extracted with ethyl acetate and water. The ethyl acetate layer was collected, dried over sodium sulfate, filtered, and concentrated in vacuo . The residue was purified on silica gel chromatography to produce a solid.
  • Step 3 The product of Step 2 (0.27 g, 0.80 mmol) was heated in N,O-bis(trimethylsilyl)acetamide (10 mL, 40.4 mmol) at 120 °C overnight. The reaction mixture was cooled, and then poured on ice water and stirred for 4h. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel chromatography to produce a solid.
  • step 2 The product of step 1 (0.22g, 0.66 mmol) was combined with 1-(4-methoxyethoxyphenyl)piperazine (0.31 g, 1.32 mmol) in dimethylformamide (2.0 mL) in a sealed tube and heated at 110 °C overnight. The reaction mixture was cooled and extracted with ethyl acetate and brine. The ethyl acetate layer was collected, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue C was purified on silica gel chromatography.
  • Step 1 To 4-(4-methoxyphenyl)butyric acid (2.00 g, 10.3 mmol) in CH 2 Cl 2 (10 mL) add SOCl 2 (3.56 g, 30 mmol). Stir 3 h and concentrate. Add 2,2-dimethyl-1,3-dioxan-4.6-dione (1.78 g, 12.4 mmol), pyridine (2.37 g. 31 mmol) and CH 2 Cl 2 (10 mL). Stir 18 h. add EtOH (10 mL), and heat at reflux 5 h. Add water, extract with EtOAc and chromatograph to obtain the ketone as an oil.
  • Step 2 Combine the product of Step 1 (0.366 g, 1.39 mmol) and guanidine carbonate (0.382 g, 2.12 mmol) in EtOH (3 mL). Heat at reflux 18 h. Add water (20 mL), cool in ice, and filter. Dry, wash with hexane and filter to obtain the pyrimidine as a solid.
  • Step 3 Add the product of Step 2 (0.15 g, 0.58 mmol) to POCl 3 (1.22 mL). Heat at reflux 1 h, concentrate, treat with ice, neutralize with NH 3 , and extract with EtOAc. Purify on PLC to obtain the chloropyrimidine as a solid.
  • Step 4 Combine the product of Step 3,2-furoic hydrazide and 1.0N HCl in EtOH. Heat in a sealed tube at 90 °C for 16 h. Basify with NH 3 , extract with EtOAc, and purify on PLC to obtain the hydrazide as a solid.
  • Step 5 Add the product of Step 4 to BSA. Heat at 120 °C 18 h. Pour into CH 3 OH, concentrate, and purify on PLC to obtain the title compound as a solid. Mass Spectrum (ESI): 350
  • Step 6 The product of Step 5 F (45 mg, 0.09 mmol) was heated in N,O-bis(trimethylsilyl)acetamide (2 mL) at 120 °C overnight. The reaction mixture was cooled, poured onto ice water and stirred for 4h. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo . The residue was purified on silica gel chromatography to produce a solid G.
  • Step 2 To a stirred solution of the product from Step 1 B (7.35g, 24.32 mmol) in diethyl ether (125 mL) under an inert atmosphere at -78 °C, a 2.5N solution of n -butyl lithium in hexanes (14.51 mL) was added dropwise. After stirring 10 minutes, triisopropyl borate (11.02 mL, 47.75 mmol) was added and the solution was warmed to room temperature and stirred for an additional 1 h. The reaction was quenched with water. The reaction mixture was concentrated in vacuo and the resulting solid intermediate was used in the next step without further purification.
  • Step 4 The product of Step 3 D (2.04 g, 4.63 mmol) was heated in N,O-bis(trimethylsilyl)acetamide (15 mL) at 120 °C overnight. The reaction mixture was cooled, poured on ice water and stirred for 4h. The mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo . The residue was purified on silica gel chromatography to produce a solid E . Mass spectrum (ESI): 309.1, 1 H NMR (CDCl 3 ) ⁇ 9.19 (s, 1H), 8.59 (s, 2H), 8.53 (s. 1H), 7.76 (s, 1H), 7.52 (s, 1H), 6.66 (m, 1H), 4.76 (s, 2H).
  • Step 1 A mixture of bromide (7.0 g, 24.37 mmol), N-Boc piperazine (5.45 g, 29.24 mmol), palladium acetate (0.22 g, 0.97 mmol), tris( tert -butyl)phosphine (0.79 g, 3.9. mmol) and sodium tert -butoxide (3.28 g, 34.12 mmol) in toluene (50 mL) was heated at reflux for 2 h under a nitrogen atmosphere, cooled to room temperature and then diluted with water. The resultant mixture was extracted by ethyl acetate, dried by sodium sulfate and filtered. This was evaporated under reduced pressure leaving a clean product B which was not purified for its use in Step 2.
  • Step 2 The compound from step 1 B was treated with tetrabutylammonium fluoride (48.74 g, 48.74 mmol of 1.0M solution in THF) in THF (100 mL) for 1 hr at room temperature, diluted with water, then extracted by ethyl acetate. The resultant ethyl acetate extract was dried with sodium sulfate and evaporated to give a phenol derivative C .
  • Step 3 Triflic anhydride was added dropwise to a mixture of phenol from step 2 C and triethyl amine (3. 74 mL, 26.81 mmol) in dichloromethane (100 mL) at 0 °C under N 2 , stirred at this temperature for 1 h and then warmed to room temperature. Saturated sodium bicarbonate solution was added and extracted by dichloromethane. This was dried using sodium sulfate and adsorbed on a small amount of silica gel, transferred to a column and eluted using hexane/ethyl acetate (4:1) to provide the triflate D .
  • Step 4 The compound from step 3 D was treated with bis(pinacolato)diboron in the presence of PdCl 2 (dppf), dppf, and potassium acetate in 1,4-dioxane (90 mL) at 80 °C under N 2 overnight, cooled to room temperature, washed with brine, dried with sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the product E . Mass spectrum (ESI), M +1 : 389.1
  • Step 5 The compound from step 4 E was treated with 2-amino-4,6-dichloro-pyrimidine as in step 1, example 4, to form compound F .
  • Step 6 The same procedure as step 2 of example 4 was performed to form compound G .
  • Step 7 The same procedure as step 3 of example 4 was performed to form compound H.
  • 1 H NMR (CDCl 3 ) ⁇ 7.61 (m, 2H), 7.43(d, 1 H), 7.38(m, 2H), 7.12 (m, 1 H), 7.02 (dd, 1H), 6.60 (dd, 1H), 6.02(br. s, 2H), 3.62 (m, 4H), 3.21 (m, 4H), 1.50 (s, 9H).
  • Step 2 The product of Step 1 B (5.70g, 19.79 mmol), 3-hydroxyphenyl boronic acid (6.10 g, 27.71 mmol), lithium chloride (2.50 g. 58.98 mmol), a 2N aqueous sodium carbonate solution (27.70 mL), and tetrakis (triphenylphosphine) palladium (1.14 g, 0.98 mmol) in 100 mL of dimethoxyethane was heated at reflux temperature for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with dichloromethane and washed with 100 mL of a mixture of 6% ammonium hydroxide in 2 N sodium carbonate solution.
  • STEP 5 A solution of the product of Step 4 E (0.60g, 1.75 mmol) and 2-furoic hydrizide (0.33g, 2.62 mmol) in 15 mL of n-butanol was heated at 90 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo . The residue was taken up in 5 mL of N,O-bis(trimethylsilyl)acetamide and heated to 120 °C under a nitrogen atmosphere for 3 h. The mixture was cooled, poured onto ice water, and then stirred 4 h. The mixture was extracted with ethyl acetate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo .
  • Step 4 The product from Step 3 D (0.37 mg, 1.08 mmol was taken up in 5 mL of N,O-bis(trimethylsilyl)acetamide and heated to 120 °C under a nitrogen atmosphere for 3 h. The mixture was cooled, poured onto ice water, and then stirred 4 h. The mixture was extracted with ethyl acetate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo . The residue was purified by silica gel chromatography to afford the compound E. Mass Spectrum (ESI): 322.1. 1 H NMR (CDCl 3 ) ⁇ 8.05 (s, 1H).
  • step 7 The compound from Example 10, step 7 was deprotected by treatment with a 4.0 M solution of HCl in dioxane at room temperature overnight or with a 50 % TFA solution in dichloromethane for 30 min. under N 2 , evaporated under reduced pressure and used without further purification.
  • 1 H NMR (DMSO-d 6 ) ⁇ 7.97 (br.s, 2H), 7.94 (s, 1H), 7.64 (s, 1H), 7.50 (m, 2H), 7.30 (t, 1H), 7.08 (dd, 1H), 7.00 (dd, 1H), 6.70 (dd, 1H), 3.70 (br.s, 1H), 3.08 (m, 4H), 2.90 (m, 4H).
  • Step 1 To a solution of the product from Example 18 and diisopropylethylamine in DMF (5 mL) was added chloroacetyl chloride dropwise at 0 °C under N 2 . The mixture was warmed to room temperature and stirred overnight. Water was then added and the resultant extracted by ethyl acetate, dried by sodium sulfate and evaporated. Purification was performed using column chromatography on silica gel using ethyl acetate to provide the intermediate B . Mass spectrum (ESI), M +1 : 438.1.
  • Step 2 Compound B from step 1(0.11g, 0.25 mmol) was treated with excess piperidine (10 equivalents) in DMF (5 mL) at room temperature under N 2 , overnight. The mixture was evaporated under reduced pressure and the product C was purified by preparative TLC using ethyl acetate/methanol (9:1). 1 H NMR (CDCl 3 ) ⁇ 7.59(m, 1H), 7.54 (m, 1H), 7.40 (d, 1H), 7.33 (m, 2H), 7.20 (m, 1H), 6.97 (dd, 1H), 6.55 (dd, 1H), 6.17 (br.
  • Step 1 To a solution of the product from Example 18 (0.145g, 0.4 mmol) and benzaldehyde (0.047g, 0.44 mmol) in dichloromethane (10 mL), was added sodium triacetoxyborohydride (0.127g, 0.6 mmol) at room temperature under N 2 . After 5 h, a 2.0 M solution of sodium hydroxide was added and the resultant extracted by dichloromethane, dried by sodium sulfate and evaporated. Purification by Prep. TLC led to the product.
  • Step 1 To a solution of the product from Example 18 (1.22 g, 3.38 mmol) and chloroacetaldehyde (0.64g, 4.06 mmol of 50% solution in water) in dichloromethane (60 mL), was added sodium triacetoxyborohydride (1.08g, 5.07mmol) at room temperature under N 2 . After 5 h, a 2.0 M solution of sodium hydroxide was added and the resultant compound B was extracted by dichloromethane, dried by sodium sulfate and evaporated. Purification performed by column chromatography. Mass spectrum (ESI) M +1 : 424.1
  • Step 2 The compound from step 1 B (0.09, 0.21 mmol) was treated with excess morpholine (10 equivalents) in DMF (5 mL) at room temperature under N 2 , overnight. The mixture was evaporated under reduced pressure and purified by preparative TLC using ethyl acetate/methanol (9:1) resulting in compound C .
  • Example 18 The product of Example 18 (0.10g, 0.28 mmol) was heated with 1-fluoro-2-nitrobenzene (0.079g, 0.56 mmol) and triethylamine (0.085g, 0.84 mmol) in DMF (5 mL) at 100 °C under N 2 for a period of 12 h. The mixture was evaporated under reduced pressure and purified by preparative TLC using ethyl acetate/hexane(7:3).
  • Step 1 A mixture of 2-amino-6-chloro-4-pyrimidinol monohydrate (2.0g, 13.74 mmol) and 2-furoic hydrazide (1.91g, 15.12 mmol) was heated in n -butanol (50 mL) at 100 °C for 20 h. The mixture was concentrated under vacuum to provide a solid residue B that was used without purification.
  • Step 2 The product of step 1 B (3.24g, 13.74 mmol) was heated in N,O-bis(trimethylsilyl)acetamide (20.5 mL, 82.44 mmol) at 120 °C overnight. The mixture was cooled, and then methanol and water were slowly added and heated to reflux for 4 h. The resulting mixture was cooled to room temperature and the precipitate C was collected by filtration. Mass spectrum (ESI), M +1 : 218.0
  • Step 3 Triflic anhydride (1.52g, 5.37 mmol) was added dropwise to a solution of product from step 2 C (1.06g, 4.88 mmol) and triethylamine (0.54g, 5.37 mmol) in dichloromethane (20 mL) at 0 °C under N 2 . After 1h, the mixture was warmed to room temperature and added a saturated solution of sodium bicarbonate. The resultant mixture was extracted with dichloromethane, dried by sodium sulfate and evaporated after filtration. Column chromatography on silica gel then led to the product D . Mass spectrum (ESI), M +1 : 350.1.
  • Step 4 A mixture of product from step 3 D (0.25g, 0.72 mmol), 2-pyridyltributyltin (0.32g, 0.86 mmol), and Pd(dppf)Cl 2 (0.029g, 0.036 mmol) was heated in DMF (5 mL) at 80 °C for 64 h under N 2 . Water was added followed by extraction with ethyl acetate, drying with sodium sulfate and then filtering. The residue E after evaporation was purified by chromatography on silica gel. 1 H NMR (DMSO-d 6 ) ⁇ 8.70(dd, 1H), 8.30 (d, 1H), 8.01 (br. S, 2H), 7.95 (m, 2H), 7.82 (s, 1H), 7.47 (m, 1H), 7.22 (dd, 1H), 6.72 (dd, 1H). Mass spectrum (ESI), M +1 : 279.0
  • Step 1 A mixture of 2-hydroxymethyl-5-bromopyridine (2.17 g, 11.54 mmol), bis(pinacolato)diboron (2.93g, 11.54 mmol), PdCl 2 (dppf) (0.57g, 0.69 mmol), and potassium acetate (3.40g, 34.62 mmol) was heated in 1,4-dioxane (65 mL) at 80 °C under N 2 overnight. The mixture was cooled to room temperature, then 2-amino-4,6-dichloro-pyrimidine (3.79g, 23.08 mmol) and a 2.0 M solution of sodium bicarbonate (6.12g in 20 mL of water) were added.
  • Step 1 To a solution of 3-chlorophenol (0.062g, 0.48 mmol) and sodium hydride (0.058g, 1.44 mmol of 60% NaH in mineral oil) in DMF (5 mL) at room temperature under N 2 , was added the product of step 1 example 22 (0.11g, 0.24 mmol) and the mixture was stirred overnight. Water was then added and the mixture was extracted by ethyl acetate, dried by sodium sulfate, filtered and concentrated under vacuum. Purification by preparative TLC on silica gel using ethyl acetate gave the product.
  • Step 5 The product of Step 4 E (250 mg, 0.59 mmol) was treated with 2-amino-4,6-dichloropyrimidine (195 mg, 1.18 mmol) as in Example 4, Step 1 (except 4 eq. of Na 2 CO 3 was used) to afford F .
  • Step 6 The product of Step 5 F (155 mg, 0.37 mmol) was combined with 2-furoic hydrazide (60 mg, 0.48 mmol) in n BuOH (3 mL). The mixture was stirred and heated at 110 °C for 20 h. The temperature was cooled to room temperature, and concentrated in vacuo to afford a solid G , which was carried on without further purification.
  • Step 7 The product of Step 6 G was combined (188 mg, 0.37 mmol) with N,O-bis(trimethylsilyl)acetamide (1.65 g, 8.5 mmol). The mixture was stirred and heated at 110 °C for 4 h under N 2 . The mixture was cooled to room temperature and concentrated in vacuo . The residue was taken up in 2:1 H 2 O/MeOH, heated at 100 °C for 2 h, concentrated in vacuo and partitioned between H 2 O and EtOAc. The organics were washed with brine, dried over MgSO 4 , filtered, concentrated in vacuo , and chromatographed to afford a solid H.
  • Example 30 The product of Example 30, Step 7 (54 mg, 0.11 mmol), was combined in ammonium acetate (7 mg, 0.091 mmol), and 10% Pd/C (8 mg) in MeOH (3 mL). The mixture was stirred under H 2 at atmospheric pressure and room temperature for 3 h. The mixture was filtered over celite, and the filtrate was concentrated in vacuo . The filtrate was partitioned between sat'd NaHCO 3 and CH 2 Cl 2 . The organics were washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to afford a solid.
  • Step 2 The product of Step 1 B (1.04 g, 6.86 mmol), 2,4-difluorophenylpiperazine (1.24 g, 6.24 mmol), K 2 CO 3 (2.59 g, 19 mmol), and KI (1.04 g, 6.24 mmol) were combined in CH 3 CN (75 mL) and refluxed under N 2 for 20 h. The mixture was filtered, concentrated in vacuo , and chromatographed on silica gel to afford C . Mass spectrum (ESI): 314.1
  • Step 4 The product of Step 3 D (270 mg, 0.85 mmol) was combined with the product of Example 2, Step 2 (100 mg, 0.43 mmol) as in Example 32 to afford a solid E.
  • Step 2 The product of Step 1 B (223 mg, 0.71 mmol), MeOH (3 mL), THF (3 mL), 25% NH 4 OH (aq) (3 mL), and Raney nickel were combined, washed wet with EtOH, (0.050 g) in a Parr bottle and hydrogenated under 50 psi for 24 h. The mixture was filtered over celite and the filtrate was concentrated in vacuo to afford a solid C , which was carried on without further purification.
  • Step 3 The product of Step 2 C (230 mg, 0.72 mmol) and the product of Example 2, Step 2 (85 mg, 0.36 mmol) were combined as in Example 32 to afford a solid D .
  • Step 3 The product of Step 2 (152 mg. 0.85 mmol) and the product of Example 2, Step 2 (100 mg, 0.43 mmol) were combined as in Example 32 to afford an oil D .
  • Step 3 The product of Step 2 C (160 mg, 0.77 mmol) was combined with the product of Example 2, Step 2 (90 mg, 0.38 mmol) as in Example 32 to afford a solid D.
  • Step 4 The product of Step 3 D (235 mg, 1.0 mmol) and the product of Example 2. Step 2 (119 mg, 0.50 mmol) were combined as in Example 32 to afford a solid E .
  • Preferred compounds of this invention include, but are not limited to, the following compounds selected from the group consisting of:
  • the pharmacological activity of the compounds of the invention is determined by the following in vitro and in vivo assays to measure A 2a receptor activity.
  • Total assay volume is 200 ⁇ l.
  • mice Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200 g are used.
  • the cataleptic state is induced by the subcutaneous administration of the dopamine receptor antagonist haloperidol (1 mg/kg, sc), 90 min before testing the animals on the vertical grid test.
  • the rats are placed on the wire mesh cover of a 25x43 plexiglass cage placed at an angle of about 70 degrees with the bench table.
  • the rat is placed on the grid with all four legs abducted and extended ("frog posture").
  • the use of such an unnatural posture is essential for the specificity of this test for catalepsy.
  • the time span from placement of the paws until the first complete removal of one paw ( decent latency ) is measured maximally for 120 sec.
  • the selective A 2A adenosine antagonists under evaluation are administered orally at doses ranging between 0.03 and 3 mg/kg, 1 and 4 h before scoring the animals.
  • Rats Male male Sprague-Dowley rats (Charles River, Calco, Como, Italy), weighing 275-300 g, are used in all experiments. The rats are housed in groups of 4 per cage, with free access to food and water, under controlled temperature and 12 hour light/dark cycle. The day before the surgery the rats are fasted over night with water ad libitum .
  • Unilateral 6-hydroxydopamine (6-OHDA) lesion of the middle forebrain bundle is performed according to the method described by Ungerstedt et al. (Brain Research, 1971, 6-OHDA and Cathecolamine Neurons, North Holland, Amsterdam, 101-127), with minor changes. Briefly, the animals are anaesthetized with chloral hydrate (400 mg/kg, ip) and treated with desipramine (10 mpk, ip) 30 min prior to 6-OHDA injection in order to block the uptake of the toxin by the noradrenergic terminals. Then, the animals are placed in a stereotaxic frame.
  • the skin over the skull is reflected and the stereotaxic coordinates (-2.2 posterior from bregma (AP), +1.5 lateral from bregma (ML), 7.8 ventral from dura (DV) are taken, according to the atlas of Pellegrino et al (Pellegrino L.J., Pellegrino A.S. and Cushman A.J., A Stereotaxic Atlas of the Rat Brain , 1979, New York: Plenum Press).
  • a burr hole is then placed in the skull over the lesion site and a needle, attached to a Hamilton syringe, is lowered into the left MFB.
  • rats Two weeks after the lesion the rats are administered with L-DOPA (50 mg/kg, ip) plus Benserazide (25 mg/kg, ip) and selected on the basis of the number of full contralateral turns quantified in the 2 h testing period by automated rotameters ( priming test ) . Any rat not showing at least 200 complete turns /2h is not included in the study.
  • Selected rats receive the test drug 3 days after the priming test (maximal dopamine receptor supersensitivity).
  • the new A 2A receptor antagonists are administered orally at dose levels ranging between 0.1 and 3 mg/kg at different time points (i.e., 1, 6, 12 h) before the injection of a subthreshold dose of L-DOPA (4 mpk, ip) plus benserazide (4 mpk, ip) and the evaluation of turning behavior.

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Abstract

L'invention concerne des composés de formule développée (I) ou des sels acceptables sur le plan pharmaceutique ou des solvates de ceux-ci, dans laquelle R, R2 et R3 sont tels que définis dans la description, ainsi que des compositions pharmaceutiques de ceux-ci et des méthodes de traitement d'accident vasculaire cérébral et de maladies du système nerveux central consistant à administrer le composé selon l'invention à un patient nécessitant un tel traitement.

Claims (15)

  1. Composé de formule structurale I :
    Figure imgb0150
     ou sel ou solvat, pharmacologiquement admissible, d'un tel composé, dans laquelle formule :
    - R représente une entité choisie dans l'ensemble constitué par les groupes R4-hétéroaryle, R5-phényle, cycloalcényle en C4-6, -C(=CH2)CH3, -C≡C-CH3,
    Figure imgb0151
     -CH=C(CH3)2,
    Figure imgb0152
     et -CH=CH-CH3 ;
    - R2 représente un reste symbolisé par -W-X ;
    - R3 représente une entité choisie dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle, trifluorométhyle, alcoxy, alcoxyalkyle, hydroxyalkyle, alkylamino, alkylaminoalkyle, dialkylamino, dialkylaminoalkyle, aminoalkyle, aryle, hétéroaryle et cyano ;
    - R4 représente 1 à 3 substituants qui peuvent être idsentiques ou différents et qui sont indépendamment choisis dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6, -CF3, -NO2, -NR15R16, alcoxy en C1-6, alkylthio en C1-6, alkylsulfinyle en C1-6, alkylsulfonyle en C1-6, -COOR17 et -C(O)NR6R7 ;
    - R5 représente 1 à 5 substituants qui peuvent être idsentiques ou différents et qui sont indépendamment choisis dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6, hydroxy, alcoxy en C1-6, -CN, -NH2, (alkyle en C1-6)amino, di(alkyle en C1-6)amino, -CF3, -OCF3, -S(O)0,2-alkyle en C1-6 et -CH2-SO2-phényle ;
    - R6 et R7 représentent des entités qui peuvent être identiques ou différentes et qui sont indépendamment choisies dans l'ensemble constitué par l'atome d'hydrogène et les groupes alkyle en C1-6;
    - R8 représente 1 à 5 substituants qui peuvent être identiques ou différents et qui sont indépendamment choisis dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6, hydroxy, alcoxy en C1-6, -CN, amino, di(alkyle en C1-6)amino, -CF3, -OCF3, acétyle, -NO2, hydroxy-alcoxy en C1-6, (alcoxy en C1-6)-alcoxy en C1-6, di(alcoxy en C1-6)alcoxy en C1-6, (alcoxy en C1-6)-(alcoxy en C1-6)-alcoxy on C1-6, carboxy-alcoxy en C1-6, (alcoxy en C1-6)-carbonyl-alcoxy en C1-6, (cycloalkyle en C3-6)-alcoxy en C1-6, di(alkyle en C1-6)-amino-alcoxy en C1-6, morpholinyle, (alkyle en C1-6)-SO2-, (alkyle en C1-6)-SO2-alcoxy en C1-6, tétrahydropyranyloxy, (alkyle en C1-6)-carbonyl-alcoxy en C1-6, (alcoxy en C1-6)-carbonyle, (alkyle en C1-6)-carbonyloxy-alcoxy en C1-6, -SO2NH2, phénoxy,
    Figure imgb0153
    Figure imgb0154
     -O-CH2-P(O)(OR6)2 et -P(O)(OR6)2,
    ou encore des substituants adjacents représentés par R8 constituent ensemble un groupe -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O- ou -O-CF2CF2-O- et forment un cycle avec les atomes de carbone auxquels ils sont liés ;
    - R9 représente une entité choisie dans l'ensemble constitué par les groupes alkyle en C1-6, R8-aryle, R8-aryl-alkyle en C1-6, thiényle, pyridyle, cycloalkyle en C3-6, (alkyle en C1-6)-OC(O)-NH-alkyle en C1-6, di(alkyle en C1-6)aminométhyle, hétérocycloalkyl-alkyle en C1-6, aryloxy-alkyle en C1-6, (alcoxy en C1-6)-alkyle en C1-6 et
    Figure imgb0155
    - R10 représente 1 à 2 substituants qui peuvent être identiques ou différents et qui sont indépendamment choisis dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6, R5-aryle et R4-hétéroaryle, deux substituants R10 placés sur un même atome de carbone pouvant aussi constituer un substituant oxo =O ;
    - R11 représente un atome d'hydrogène ou un groupe alkyle en C1-6 ou
    - C(O)-alkyle, ou bien représente, conjointement avec R17, un groupe de formule -(CH2)p-A-(CH2)q- où p et q valent chacun indépendamment 2 ou 3 et A représente une liaison ou un chaînon choisi parmi -CH2-, -Set -O-, lequel groupe forme un cycle avec l'atome d'azote auquel il est rattaché ;
    - R12 représente 1 à 2 substituants qui peuvent être identiques ou différents et qui sont indépendamment choisis dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6, hydroxy, alcoxy en C1-6 et trifluorométhyle ;
    - R13 représente une entité choisie dans l'ensemble constitué par l'atome d'hydrogène et les groupes alkyle en C1-6, phényle, benzyle, alcényle en C2-6, (alcoxy en C1-6)-alkyle en C1-6, di(alkyle en C1-6)-aminoalkyle en C1-6, pyrrolidinyl-alkyle en C1-6 et pipéridino-alkyle en C1-6 ;
    - R14 représente une entité choisie dans l'ensemble constitué par les atomes d'hydrogène et d'halogène et les groupes alkyle en C1-6 et alcoxy en C1-6 ;
    - R15 représente une entité choisie dans l'ensemble constitué par l'atome d'hydrogène et les groupes alkyle en C1-6 ;
    - R16 représente une entité choisie dans l'ensemble constitué par l'atome d'hydrogène et les groupes (alkyle en C1-6)-carbonyle et (alkyle en C1-6)-sulfonyle ;
    - R17 représente une entité choisie dans l'ensemble constitué par les groupes alkyle en C1-6, hydroxyalkyle en C1-6, cycloalkyle en C3-6, (alcoxy en C1-6)-alcoxy en C1-6, alcoxy en C1-6, (alcoxy en C1-6)-alkyle en C1-6, allyle, propargyle, R8-hétéroaryle, R8-aryle et R8-aryl-alkyle en C1-6 ;
    - R18 représente une liaison ou un chaînon ou raccord choisi parmi -CH2-, -CHOH-, -CH(CH3)-, -C(CH3)2-, -(CH2)n- et -O(CH2)n-;
    - Q et Q1 représentent des entités qui peuvent être identiques ou différentes et qui sont choisies indépendamment parmi
    Figure imgb0156
    - m et n valent chacun indépendamment de 1 à 3 ;
    - p et q valent chacun indépendamment de 0 à 2 ;
    - s vaut de 0 à 4 ;
    - W représente un groupe aryle ou hétéroaryle comportant 1 à 3 hétéroatomes, qui peuvent être identiques ou différents et sont choisis indépendamment parmi les atomes d'azote, de soufre et d'oxygène, lequel groupe aryle ou hétéroaryle peut, en option, porter 1 à 3 substituants qui peuvent être identiques ou différents et sont choisis indépendamment dans l'ensemble constitué par les atomes d'halogène et les groupes alkyle, aryle, alkyl-cycloalkyle, hydroxy, hydxoxyalkyle, alcoxy, alcoxy-alkyle, alcoxy-alcoxy, -NR6R7, alcényle en C2-6 et cyano ;
    - X représente une entité choisie dans l'ensemble constitué par l'atome d'hydrogène et les groupes amino, diméthylamino, -N(R6)-(CH2)s-aryle, -N(R6)-(CH2)s-hétéroaryle et -N(R6)-(CH2)m+1-OH, ou bien encore X représente -R18-Y-Z ;
    - Y représente un chaînon ou raccord choisi dans l'ensemble constitué par -N(R6)-CH2CH2-N(R7)-, -N(R6)-(CH2)n-aryle-, -OCH2CH2-N(R6)-, -O-, -S-, -CH2S-, -(CH2)2-3-N(R6)-, R8-hétéroaryle divalent
    Figure imgb0157
    - et Z représente une entité choisie dans l'ensemble constitué par l'atome d'hydrogène et les groupes alkyle, alcoxyalkyle, R8-aryle, R8-aryl-alkyle en C1-6, R8-hétéroaryle, R8-bicycloalkyle, aminoalkyle, alkylamino, amino, -N(R5)-(CH2)5-aryle, -N(R6)-(CH2)3-hétéroaryle, -N(R6)-C(=O)-OR17, alkyl-hétérocycloalkyle, hétérocycloalkyle, hétérocycloalkyl-alkyle, alcoxy-hétérocycloalkyle, hécéroaryle. R8-benzohétéroaryle à cycles condensés, diphénylméthyle et R9-C(=O)-,
    et en outre, si Y représente
    Figure imgb0158
    Z peut aussi représenter un groupe hydroxy, R9-SO2-, R17-N(R11)-(CH2)s-C(=O)-, R17-O-C(=O)-, R17-C-(CH2)n-C(=O)-, (benzohétéroaryle à cycles condensés)-(CH2)n-C(=O)-, (benzohétéroaryle à cycles condensés)-(CH2)n- ou R17-N(R11)-C(=S)-, et en outre, si Q représente
    Figure imgb0159
     Z peut aussi représenter un groupe R17R11N-, phénylamino ou pyridylamino ;
    - ou Z et Y représentent conjointement un groupe choisi dans l'ensemble constitué par les suivants :
    Figure imgb0160
    Figure imgb0161
    Figure imgb0162
    Figure imgb0163
    Figure imgb0164
     ou son N-oxyde,
    Figure imgb0165
    Figure imgb0166
     étant entendu que, sauf indication contraire,
    - le terme "groupe alkyle", y compris dans le cas des fragments alkyle des groupes alcoxy, alkylamino et dialkylamino, désigne un groupe hydrocarboné aliphatique qui peut être linéaire ou ramifié et comporte de 1 à 20 atomes de carbone,
    - le terme "halogène" désigne fluor, chlore, brome ou iode,
    - le terme "groupe alcoxy" désigne un groupe -O-alkyle, où le terme "alkyle" a la signification indiquée ci-dessus,
    - le terme "groupe alcényle" désigne un groupe hydrocarboné aliphatique qui contient au moins une double liaison carbone-carbone, qui peut être linéaire ou ramifié et qui comporte de 2 à 15 atomes de carbone,
    - le terme "groupe alcanoyle", désigne un groupe alkyle lié à un groupe carbonyle, où le terme "alkyle" a la signification indiquée ci-dessus,
    - le terme "groupe cycloalkyle" désigne un système cyclique non-aromatique, monocyclique ou polycyclique à cycles condensés, comportant de 3 à 10 atomes de carbone de cycle,
    - le terme "groupe hétérocycloalkyle" désigne un système cyclique non-aromatique, monocyclique ou polycyclique à cycles condensés, comportant de 3 à 10 atomes de carbone de cycle, et comportant 1 ou 2 hétéro-atomes choisis indépendamment parmi les atomes d'oxygène, de soufre et d'azote, lequel ou lesquels bétéroatome(s) est ou sont inséré(s) dans une structure carbocyclique, sous réserve qu'il n'y ait pas deux atomes de soufre et/ou d'oxygène adjacents dans les cycles,
    - le terme "groupe aryle" désigne un système cyclique aromatique, monocyclique ou polycyclique, comportant de 6 à 14 atomes do carbone de cycle,
    - le terme "groupe hétéroaryle" désigne un groupe cyclique aromatique comportant 5 ou 6 atomes de cycle ou un groupe bicyclique aromatique comportant 11 à 12 atomes de cycle, et comportant 1 ou 2 hétéroatomes choisis indépendamment parmi les atomes d'oxygène, de soufre et d'azote, lequel ou lesquels hétéroatome(s) est ou sont inséré(s) dans une structure carbocyclique et apportent un nombre suffisant d'électrons π délocalisés pour conférer au groupe le caractère aromatique, sous réserve qu'il n'y ait pas deux atomes de soufre et/ou d'oxygène adjacents dans les cycles.
  2. Composé conforme à la revendication 1, dans lequel R représente
    Figure imgb0167
  3. Composé conforme à la revendication 1, dans lequel R3 représente un atome d'hydrogène.
  4. Composé conforme à la revendication 1, dans lequel R représente
    Figure imgb0168
     et R3 représente un atome d'hydrogène.
  5. Composé conforme à la revendication 1, choisi dans l'ensemble constitué par les composés n° 2 à 36, 38, 40 à 66, 78 à 86 et 88 à 151 des Exemples 2 à 31.
  6. Composé conforme à la revendication 5, choisi dans l'ensemble constitué par les suivants :
    Figure imgb0169
    Figure imgb0170
    Figure imgb0171
  7. Composition pharmaceutique comprenant un ou plusieurs composés conformes à la revendication 1 et un ou plusieurs véhicules pharmaco-logiquement admissibles.
  8. Composition pharmaceutique conforme à la revendication 7, qui comprend en outre un ou plusieurs autres agents servant à traiter la maladie de Parkinson.
  9. Composition pharmaceutique conforme à la revendication 8, dans laquelle ledit ou lesdits autres agents servant à traiter la maladie de Parkinson sont choisis dans l'ensemble constitué par la L-dopa, les agonistes dopaminergiques, les inhibiteurs de la monoamine oxydase B, les inhibiteurs de la dopa décarboxylase, et les inhibiteurs de la catéchol O-méthyl-transférase.
  10. Emploi d'un ou de plusieurs composés conformes à la revendication 1 dans la fabrication d'une composition pharmaceutique destinée au traitement d'une attaque ou d'une maladie du système nerveux central.
  11. Emploi conforme à la revendication 10, ladite maladie du système nerveux central étant une maladie cognitive ou une maladie neuro-dégénérative.
  12. Emploi conforme à la revendication 10, ladite maladie du système nerveux central étant la maladie de Parkinson, la démence sénile ou une psychose d'origine organique.
  13. Emploi conforme à la revendication 12, ladite maladie du système nerveux central étant la maladie de Parkinson.
  14. Emploi conforme à la revendication 13, le traitement comportant en outre le fait d'administrer un ou plusieurs autres agents servant à traiter la maladie de Parkinson, qui peuvent être le même agent ou des agents différents et sont choisis indépendamment dans l'ensemble constitué par la L-dopa, les agonistes dopaminergiques, les inhibiteurs de la monoamine oxydase B, les inhibiteurs de la dopa décarboxylase, et les inhibiteurs de la catéchol O-méthyl-transférase.
  15. Trousse comprenant, dans des compartiments séparés au sein d'un unique emballage, des compositions pharmaceutiques destinées à être utilisées en combinaison pour traiter la maladie de Parkinson, dans laquelle un compartiment contient une composition pharmaceutique comprenant un ou plusieurs composés de formule I indiquée dans la revendication 1, avec un ou plusieurs véhicules pharmacologiquement admissibles, et dans laquelle il y a, dans des compartiments distincts, une ou plusieurs compositions pharmaceutiques comprenant chacune un ou plusieurs autres agents servant à traiter la maladie de Parkinson, avec un ou plusieurs véhicules pharmacologiquement admissibles.
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